Target Assisted Combinatorial Synthesis (TACS) is a new method to identify pharmacophores, collections of functional groups that confer binding ability to a specific target, and from there to develop lead compounds for drug development.. In a TACS experiment, a therapeutic target is presented with a library of n fragments prepared by convergent chemical synthesis. Composites of these fragments are then formed by reaction between the reactive groups of two or more fragments in the library under conditions of dynamic equilibrium. The target then selects the tightest binding composite (the preferred composite) from a pool of n2 composite compounds prepared in situ. With 104 to 105 (n) ligand fragments in a typical library, the effective library sizes explored in a TACS experiment are 108-1010 compounds (n2) in a "two-fold compositing" TACS experiment, and still more when three or more fragments are assembled in a composite. The TACS method thereby allows exploration of vast regions of structure space for pharmacophores and their combinations, yet prepares analyzable quantities of fragments, and does not require significantly more target than a classical screening or combinatorial experiment directed against a library supported on beads. Supporting the analysis of TACS experiments is Fourier Transform Ion Cyclotron Resonance Mass Spectrometry (FT-ICR MS), stored waveform inverse Fourier transform (SWIFT), and infrared multiphoton laser disassociation (IRMPD). Together, these generate information about the structure of a target-bound composite in a single experiment. The goal of this proposal is to develop the TACS strategy to the point where it is selected by medicinal chemists for targets for which it is appropriate, and use TACS to address several issues in Diversity Science. We target two families of biological molecules of biomedical interest: (a) the Src homology 2 (SH2) domain family, whose members are important in cell regulation, cancer, and a variety of other diseases; (b) the eosinophil cationic proteirdeosinophil-derived neurotoxin (ECP/EDN) family, which plays key roles in allergy, anaphylaxis, and inflammation. Fragment libraries include trialkoxyphosphines, diols, and diamines, which will be prepared using phosphite ester chemistry, metathesis, thiamin condensation and peptide chemistry. Compositing chemistry will involve the coordination of trialkoxyphosphines and diamines with metals, and diols with borates. These activities will generate non-peptidic lead compounds that bind to SH2 domains, non-nucleic acid lead compounds that bind to human EDN/ECP, a general, empirically based view of the scope and limitations of the TACS strategy, and a deeper understanding of structure and behavior of large diverse collections of small organic molecules.